tbuckley/cabot-search huggingface dataset:
The feasibility of oral targeted drug delivery: Gut immune to particulates?
Authors: Yuehong Ren, Wei Wu, Xingwang Zhang
Journal: Acta Pharmaceutica Sinica B (2022)

Targeted drug delivery is constantly updated with a better understanding of the physiological and pathological features of various diseases. Depending on high safety, good compliance and many other undeniable advantages, attempts have been undertaken to complete an intravenous-to-oral conversion of targeted drug delivery. However, oral delivery of particulates to systemic circulation is highly challenging due to the biochemical aggressivity and immune exclusion in the gut that restrain absorption and access to the bloodstream. Little is known about the feasibility of targeted drug delivery via oral administration (oral targeting) to a remote site beyond the gastrointestinal tract. To this end, this review proactively contributes to a special dissection on the feasibility of oral targeting. We discussed the theoretical basis of oral targeting, the biological barriers of absorption, the in vivo fate and transport mechanisms of drug vehicles, and the effect of structural evolution of vehicles on oral targeting as well. At last, a feasibility analysis on oral targeting was performed based on the integration of currently available information. The innate defense of intestinal epithelium does not allow influx of more particulates into the peripheral blood through enterocytes. Therefore, limited evidence and lacking exact quantification of systemically exposed particles fail to support much success with oral targeting. Nevertheless, the lymphatic pathway may serve as a potentially alternative portal of peroral particles into the remote target sites via M-cell uptake.
9 months of delamanid, linezolid, levofloxacin, and pyrazinamide versus conventional therapy for treatment of fluoroquinolone-sensitive multidrug-resistant tuberculosis (MDR-END): a multicentre, randomised, open-label phase 2/3 non-inferiority trial in South Korea
Authors: Jeongha Mok, Myungsun Lee, Deog Kyeom Kim, Ju Sang Kim, Byung Woo Jhun, Kyung-Wook Jo, Doosoo Jeon, Taehoon Lee, Ji Yeon Lee, Jae Seuk Park, Seung Heon Lee, Young Ae Kang, Jung-Kyu Lee, Nakwon Kwak, Joong Hyun Ahn, Tae Sun Shim, Song Yee Kim, Seungmo Kim, Kyungjong Kim, Kwang-Hyuk Seok, Soyeong Yoon, Young Ran Kim, Jisu Kim, Dahae Yim, Seokyung Hahn, Sang Nae Cho, Jae-Joon Yim
Journal: The Lancet (2022)
Erratum: Antihistone Properties of C1 Esterase Inhibitor Protect against Lung Injury
Authors: Malgorzata Wygrecka, Lukasz Wujak, Philipp Markart, Djuro Kosanovic, Holger C. Müller-Redetzky, Martin Witzenrath, Ingrid Henneke, Ralph T. Schermuly, Werner Seeger, Liliana Schaefer, Grazyna Kwapiszewska, Leigh M. Marsh, Nelli Baal, Holger Hackstein, Steven de Maat, Coen Maas
Journal: American Journal of Respiratory and Critical Care Medicine (2022)
Rearranged Endogenized Plant Pararetroviruses as Evidence of Heritable RNA-based Immunity
Authors: Adrian A Valli, Irene Gonzalo-Magro, Diego H Sanchez
Journal: Molecular Biology and Evolution (2022)

Eukaryotic genomics frequently revealed historical spontaneous endogenization events of external invading nucleic acids, such as viral elements. In plants, an extensive occurrence of endogenous plant pararetroviruses (EPRVs) is usually believed to endow hosts with an additional layer of internal suppressive weaponry. However, an actual demonstration of this activity remains speculative. We analyzed the EPRV component and accompanying silencing effectors of Solanum lycopersicum, documenting that intronic/intergenic pararetroviral integrations bearing inverted-repeats fuel the plant's RNA-based immune system with suitable transcripts capable of evoking a silencing response. A surprisingly small set of rearrangements explained a substantial fraction of pararetroviral-derived endogenous small-interfering (si)RNAs, enriched in 22-nt forms typically associated with anti-viral post-transcriptional gene silencing. We provide preliminary evidence that such genetic and immunological signals may be found in other species outside the genus Solanum. Based on molecular dating, bioinformatics, and empirical explorations, we propose that homology-dependent silencing emerging from particular immuno-competent rearranged chromosomal areas that constitute an adaptive heritable trans-acting record of past infections, with potential impact against the unlocking of plant latent EPRVs and cognate-free pararetroviruses.
Conditioning Regimens are Associated with Distinct Patterns of Microbiota Injury in Allogeneic Hematopoietic Cell Transplantation
Authors: Roni Shouval, Nicholas R. Waters, Antonio L. C. Gomes, Corrado Zuanelli Brambilla, Teng Fei, Sean M. Devlin, Chi L. Nguyen, Kate A. Markey, Anqi Dai, John B. Slingerland, Annelie G. Clurman, Emily Fontana, Luigi A. Amoretti, Roberta J. Wright, Tobias M. Hohl, Ying Taur, Anthony D. Sung, Daniela Weber, Daigo Hashimoto, Takanori Teshima, Nelson J. Chao, Ernst Holler, Michael Scordo, Sergio A. Giralt, Miguel-Angel Perales, Jonathan U. Peled, Marcel R.M. van den Brink
Journal: Clinical Cancer Research (2022)

Abstract Purpose: The gut microbiota is subject to multiple insults in allogeneic hematopoietic cell transplantation (allo-HCT) recipients. We hypothesized that preparative conditioning regimens contribute to microbiota perturbation in allo-HCT. Experimental Design: This was a retrospective study that evaluated the relationship between conditioning regimens exposure in 1,188 allo-HCT recipients and the gut microbiome. Stool samples collected from 20 days before transplantation up to 30 days after were profiled using 16S rRNA sequencing. Microbiota injury was quantified by changes in α-diversity. Results: We identified distinct patterns of microbiota injury that varied by conditioning regimen. Diversity loss was graded into three levels of conditioning-associated microbiota injury (CMBI) in a multivariable model that included antibiotic exposures. High-intensity regimens, such as total body irradiation (TBI)–thiotepa-cyclophosphamide, were associated with the greatest injury (CMBI III). In contrast, the nonmyeloablative regimen fludarabine–cyclophosphamide with low-dose TBI (Flu/Cy/TBI200) had a low-grade injury (CMBI I). The risk of acute GVHD correlated with CMBI degree. Pretransplant microbial compositions were best preserved with Flu/Cy/TBI200, whereas other regimens were associated with loss of commensal bacteria and expansion of Enterococcus. Conclusions: Our findings support an interaction between conditioning at the regimen level and the extent of microbiota injury.
Diagnostic accuracy of vaccine and vaccine excipient testing in the setting of allergic reactions to <scp>COVID</scp>‐19 vaccines: A systematic review and meta‐analysis
Authors: Matthew Greenhawt, Marcus Shaker, David B. K. Golden, Elissa M. Abrams, Kimberly G. Blumenthal, Anna R. Wolfson, Cosby A. Stone, Matthew S. Krantz, Derek K. Chu, Ben A. Dwamena
Journal: Allergy (2022)

Abstract For persons with immediate allergic reactions to mRNA COVID‐19 vaccines, skin testing (ST) to the vaccine/excipients (polyethylene glycol[PEG] and polysorbate 80 [PS]) has been recommended, but has unknown accuracy. To assess vaccine/excipient ST accuracy in predicting all‐severity immediate allergic reactions upon re‐vaccination, systematic review was performed searching Medline, EMBASE, Web of Science, and the WHO global coronavirus database (inception‐Oct 4, 2021) for studies addressing immediate (≤4 h post‐vaccination) all‐severity allergic reactions to 2nd mRNA COVID‐19 vaccination in persons with 1st dose immediate allergic reactions. Cases evaluating delayed reactions, change of vaccine platform, or revaccination without vaccine/excipient ST were excluded. Meta‐analysis of diagnostic testing accuracy was performed using Bayesian methods. The GRADE approach evaluated certainty of the evidence, and QUADAS‐2 assessed risk of bias. Among 20 studies of mRNA COVID‐19 first dose vaccine reactions, 317 individuals underwent 578 ST to any one or combination of vaccine, PEG, or PS, and were re‐vaccinated with the same vaccine. Test sensitivity for either mRNA vaccine was 0.2 (95%CrI 0.01–0.52) and specificity 0.97 (95%CrI 0.9–1). PEG test sensitivity was 0.02 (95%CrI 0.00–0.07) and specificity 0.99 (95%CrI 0.96–1). PS test sensitivity was 0.03 (95%CrI 0.00–0.0.11) and specificity 0.97 (95%CrI 0.91–1). Combined for use of any of the 3 testing agents, sensitivity was 0.03 (95%CrI 0.00–0.08) and specificity was 0.98 (95%CrI 0.95–1.00). Certainty of evidence was moderate. ST has low sensitivity but high specificity in predicting all‐severity repeat immediate allergic reactions to the same agent, among persons with 1st dose immediate allergic reactions to mRNA COVID‐19 vaccines. mRNA COVID‐19 vaccine or excipient ST has limited risk assessment utility.
Association of Serum Dupilumab Levels at 16 Weeks With Treatment Response and Adverse Effects in Patients With Atopic Dermatitis
Authors: Lotte S. Spekhorst, Marlies de Graaf, Floris Loeff, Nicolaas P. A. Zuithoff, Daphne Bakker, Celeste M. Boesjes, Judith Thijs, Roselie Achten, Femke van Wijk, Theo Rispens, Marjolein S. de Bruin-Weller
Journal: JAMA Dermatology (2022)

The registered dose of dupilumab for adult patients with atopic dermatitis (AD) is 300 mg every other week. At present, it is unknown whether serum dupilumab levels are associated with treatment response or adverse effects.To evaluate serum dupilumab levels at 16 weeks of treatment and to explore the association of serum dupilumab levels with treatment response and adverse effects in patients with AD.This clinical, prospective, observational cohort study used data from the prospective BioDay Registry including adult patients with AD who started dupilumab treatment and for whom a serum sample was available at 16 weeks of treatment. All patients were treated according to the BioDay protocol in the University Medical Center Utrecht in the Netherlands. Patients received a loading dose of dupilumab 600 mg subcutaneously, followed by 300 mg every other week. Patients who had a dose adjustment or discontinued treatment before 16 weeks of treatment were excluded. Data analyses were performed from January to June 2022.Disease severity of AD was assessed at baseline and at weeks 16 and 52 using the Eczema Area and Severity Index (EASI). Treatment response was defined as the percent reduction in EASI score vs the baseline score (eg, EASI 90 indicated a 90% reduction) and as an absolute EASI cutoff score of 7 or lower (controlled AD). Adverse effects were recorded during the first year. At 16 weeks, dupilumab serum levels and treatment responses were measured and analyzed. Multivariate logistic regression modeling was used to determine the prediction of response (EASI 90; EASI ≤7) and adverse effects at 52 weeks, with serum dupilumab levels at 16 weeks in the presence of the covariates age and sex.Among the total of 295 patients with AD (mean [SD] age, 41.5 [15.9] years; 170 [57.6%] men), the median (IQR [range]) drug level was 86.6 μg/mL (64.6-110.0 μg/mL [10.1-382.0 μg/mL]) at 16 weeks of treatment. No significant differences were found in serum dupilumab levels between responder statuses (EASI, <50, 50, 75, or 90) at week 16. Multivariate logistic regression analysis showed nonsignificant odds ratios (ORs) for serum dupilumab levels at 16 weeks regarding prediction of long-term response (EASI ≥90: OR, 0.96 [95% CI, 0.90-1.04; P = .34] and EASI ≤7: OR, 1.03 [95% CI, 0.93-1.14; P = .55]) and adverse effects (OR, 1.01 [95% CI, 0.95-1.07; P = .83]).This prospective clinical cohort study found a broad range of serum dupilumab levels at 16 weeks of treatment and no association with treatment response and adverse effects during first year of treatment. Response may be dependent on target availability of the interleukin-4 receptor subunit α, with an interpatient variability producing heterogeneity in response.
Follow-up of Patients With Keratinocyte Carcinoma
Authors: Sara Mirali, Evan Tang, Aaron M. Drucker, Irina Turchin, Melinda Gooderham, Nick Levell, Jennifer Beecker, Robert Bissonnette, Helen Catherall, Jo-Ann Lapointe McKenzie, Nicole Hawkins, Chih-Ho Hong, Sunil Kalia, Kim Papp, An-Wen Chan
Journal: JAMA Dermatology (2022)

Patients treated for cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), collectively called keratinocyte carcinoma (KC), are at risk for recurrence, metastasis, and additional primary cutaneous malignant neoplasms. It is unclear how often patients should be seen for follow-up skin examination after initial treatment of KC.To summarize the recommendations and evaluate the methodological quality of clinical practice guidelines for dermatologic follow-up of patients with BCC and invasive SCC.PubMed, MEDLINE, and Embase were searched for relevant articles published from January 2010 to March 2022. Search terms included guideline, squamous cell carcinoma, and basal cell carcinoma. National or international guidelines containing recommendations for follow-up frequency after a diagnosis of localized cutaneous KC were included. Quality was assessed using the 6 domains of the Appraisal of Guidelines Research and Evaluation II (AGREE II) tool: (1) scope and purpose; (2) stakeholder development; (3) rigor of development; (4) clarity of presentation; (5) applicability; and (6) editorial independence. The Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) was used to guide study reporting.Among the 14 guidelines meeting eligibility criteria, there was little consensus on the appropriate follow-up frequency after initial KC treatment. Overall duration of follow-up ranged from a single posttreatment visit to lifelong surveillance. Most guidelines stratified their recommendations by recurrence risk. For low-risk BCC and guidelines that did not stratify by risk, follow-up recommendations ranged from every 6 to 12 months. For high-risk BCC, 1 guideline suggested follow-up every 3 months, while 4 recommended every 6 months. For low-risk SCC, 5 guidelines recommended annual follow-up; 3 guidelines, every 6 months; and 1 guideline, every 3 months. For high-risk SCC, recommendations included a range of follow-up frequencies, spanning every 3 months (n = 5 guidelines), 4 months (n = 1), 6 months (n = 6), or annually (n = 4). One guideline did not use risk stratification and recommended annual screening. The highest scoring AGREE II domain was "scope and purpose," which assessed the guideline's overall objectives, and the lowest scoring was "applicability," which assessed barriers and facilitators to implementation.The findings of this systemic review highlight variations in follow-up recommendations for patients after initial treatment for KC. Randomized clinical trials are needed to define an optimal follow-up regimen.
The Combination of Trametinib and Ganitumab is Effective in RAS-Mutated PAX-Fusion Negative Rhabdomyosarcoma Models
Authors: Katie E. Hebron, Xiaolin Wan, Jacob S. Roth, David J. Liewehr, Nancy E. Sealover, William J.E. Frye, Angela Kim, Stacey Stauffer, Olivia L. Perkins, Wenyue Sun, Kristine A. Isanogle, Christina M. Robinson, Amy James, Parirokh Awasthi, Priya Shankarappa, Xiaoling Luo, Haiyan Lei, Donna Butcher, Roberta Smith, Elijah F. Edmondson, Jin-Qiu Chen, Noemi Kedei, Cody J. Peer, Jack F. Shern, W. Douglas Figg, Lu Chen, Matthew D. Hall, Simone Difilippantonio, Frederic G. Barr, Robert L. Kortum, Robert W. Robey, Angelina V. Vaseva, Javed Khan, Marielle E. Yohe
Journal: Clinical Cancer Research (2022)

Abstract Purpose: PAX-fusion negative rhabdomyosarcoma (FN RMS) is driven by alterations in the RAS/MAP kinase pathway and is partially responsive to MEK inhibition. Overexpression of IGF1R and its ligands is also observed in FN RMS. Preclinical and clinical studies have suggested that IGF1R is itself an important target in FN RMS. Our previous studies revealed preclinical efficacy of the MEK1/2 inhibitor, trametinib, and an IGF1R inhibitor, BMS-754807, but this combination was not pursued clinically due to intolerability in preclinical murine models. Here, we sought to identify a combination of an MEK1/2 inhibitor and IGF1R inhibitor, which would be tolerated in murine models and effective in both cell line and patient-derived xenograft models of RAS-mutant FN RMS. Experimental Design: Using proliferation and apoptosis assays, we studied the factorial effects of trametinib and ganitumab (AMG 479), a mAb with specificity for human and murine IGF1R, in a panel of RAS-mutant FN RMS cell lines. The molecular mechanism of the observed synergy was determined using conventional and capillary immunoassays. The efficacy and tolerability of trametinib/ganitumab was assessed using a panel of RAS-mutated cell-line and patient-derived RMS xenograft models. Results: Treatment with trametinib and ganitumab resulted in synergistic cellular growth inhibition in all cell lines tested and inhibition of tumor growth in four of six models of RAS-mutant RMS. The combination had little effect on body weight and did not produce thrombocytopenia, neutropenia, or hyperinsulinemia in tumor-bearing SCID beige mice. Mechanistically, ganitumab treatment prevented the phosphorylation of AKT induced by MEK inhibition alone. Therapeutic response to the combination was observed in models without a mutation in the PI3K/PTEN axis. Conclusions: We demonstrate that combined trametinib and ganitumab is effective in a genomically diverse panel of RAS-mutated FN RMS preclinical models. Our data also show that the trametinib/ganitumab combination likely has a favorable tolerability profile. These data support testing this combination in a phase I/II clinical trial for pediatric patients with relapsed or refractory RAS-mutated FN RMS.
Prognostic Impact of Unsupervised Early Assessment of Bulk and Leukemic Stem Cell Measurable Residual Disease in Acute Myeloid Leukemia
Authors: Alban Canali, Inès Vergnolle, Sarah Bertoli, Laetitia Largeaud, Marie-Laure Nicolau, Jean-Baptiste Rieu, Suzanne Tavitian, Françoise Huguet, Muriel Picard, Pierre Bories, Jean Philippe Vial, Nicolas Lechevalier, Marie Christine Béné, Isabelle Luquet, Véronique Mansat-De Mas, Eric Delabesse, Christian Récher, François Vergez
Journal: Clinical Cancer Research (2022)

Acute myeloid leukemias (AML) are clonal diseases that develop from leukemic stem cells (LSC) that carry an independent prognostic impact on the initial response to induction chemotherapy, demonstrating the clinical relevance of LSC abundance in AML. In 2018, the European LeukemiaNet published recommendations for the detection of measurable residual disease (Bulk MRD) and suggested the exploration of LSC MRD and the use of multiparametric displays.We evaluated the performance of unsupervised clustering for the post-induction assessment of bulk and LSC MRD in 155 patients with AML who received intensive conventional chemotherapy treatment.The median overall survival (OS) for Bulk+ MRD patients was 16.7 months and was not reached for negative patients (HR, 3.82; P < 0.0001). The median OS of LSC+ MRD patients was 25.0 months and not reached for negative patients (HR, 2.84; P = 0.001). Interestingly, 1-year (y) and 3-y OS were 60% and 39% in Bulk+, 91% and 52% in Bulk-LSC+ and 92% and 88% in Bulk-LSC-.In this study, we confirm the prognostic impact of post-induction multiparametric flow cytometry Bulk MRD in patients with AML. Focusing on LSCs, we identified a group of patients with negative Bulk MRD but positive LSC MRD (25.8% of our cohort) with an intermediate prognosis, demonstrating the interest of MRD analysis focusing on leukemic chemoresistant subpopulations.
Blue Turns to Gray: Paleogenomic Insights into the Evolutionary History and Extinction of the Blue Antelope (<i>Hippotragus leucophaeus</i>)
Authors: Elisabeth Hempel, Faysal Bibi, J Tyler Faith, Klaus-Peter Koepfli, Achim M Klittich, David A Duchêne, James S Brink, Daniela C Kalthoff, Love Dalén, Michael Hofreiter, Michael V Westbury
Journal: Molecular Biology and Evolution (2022)

The blue antelope (Hippotragus leucophaeus) is the only large African mammal species to have become extinct in historical times, yet no nuclear genomic information is available for this species. A recent study showed that many alleged blue antelope museum specimens are either roan (Hippotragus equinus) or sable (Hippotragus niger) antelopes, further reducing the possibilities for obtaining genomic information for this extinct species. While the blue antelope has a rich fossil record from South Africa, climatic conditions in the region are generally unfavorable to the preservation of ancient DNA. Nevertheless, we recovered two blue antelope draft genomes, one at 3.4× mean coverage from a historical specimen (∼200 years old) and one at 2.1× mean coverage from a fossil specimen dating to 9,800-9,300 cal years BP, making it currently the oldest paleogenome from Africa. Phylogenomic analyses show that blue and sable antelope are sister species, confirming previous mitogenomic results, and demonstrate ancient gene flow from roan into blue antelope. We show that blue antelope genomic diversity was much lower than in roan and sable antelope, indicative of a low population size since at least the early Holocene. This supports observations from the fossil record documenting major decreases in the abundance of blue antelope after the Pleistocene-Holocene transition. Finally, the persistence of this species throughout the Holocene despite low population size suggests that colonial-era human impact was likely the decisive factor in the blue antelope's extinction.
Optimal Frequency of Urinary Albumin Screening in Type 1 Diabetes
Authors: Bruce A. Perkins, Ionut Bebu, Ian H. de Boer, Mark Molitch, Bernard Zinman, John Bantle, Gayle M. Lorenzi, David M. Nathan, John M. Lachin
Journal: Diabetes Care (2022)

Kidney disease screening recommendations include annual urine testing for albuminuria after 5 years' duration of type 1 diabetes. We aimed to determine a simple, risk factor-based screening schedule that optimizes early detection and testing frequency.Urinary albumin excretion measurements from 1,343 participants in the Diabetes Control and Complications Trial and its long-term follow-up were used to create piecewise-exponential incidence models assuming 6-month constant hazards. Likelihood of the onset of moderately or severely elevated albuminuria (confirmed albumin excretion rate AER ≥30 or ≥300 mg/24 h, respectively) and its risk factors were used to identify individualized screening schedules. Time with undetected albuminuria and number of tests were compared with annual screening.The 3-year cumulative incidence of elevated albuminuria following normoalbuminuria at any time during the study was 3.2%, which was strongly associated with higher glycated hemoglobin (HbA1c) and AER. Personalized screening in 2 years for those with current AER ≤10 mg/24 h and HbA1c ≤8% (low risk [0.6% three-year cumulative incidence]), in 6 months for those with AER 21-30 mg/24 h or HbA1c ≥9% (high risk [8.9% three-year cumulative incidence]), and in 1 year for all others (average risk [2.4% three-year cumulative incidence]) was associated with 34.9% reduction in time with undetected albuminuria and 20.4% reduction in testing frequency as compared with annual screening. Stratification by categories of HbA1c or AER alone was associated with reductions of lesser magnitude.A personalized alternative to annual screening in type 1 diabetes can substantially reduce both the time with undetected kidney disease and the frequency of urine testing.Kidney disease screening recommendations include annual urine testing for albuminuria after 5 years' duration of type 1 diabetes. We investigated simple screening schedules that optimize early detection and testing frequency. Personalized screening in 2 years for those with current AER ≤10 mg/24 h and HbA1c ≤8%, in 6 months for those with AER 21-30 mg/24 h or HbA1c ≥9%, and in 1 year for all others yielded 34.9% reduction in time with undetected albuminuria and 20.4% fewer evaluations compared with annual screening. A personalized alternative to annual screening in type 1 diabetes can substantially reduce both the time with undetected kidney disease and the frequency of urine testing.